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Author Notes:

E-mail: chanc@nei.nih.gov

Conceived and designed the experiments: DA CCC.

Performed the experiments: DA YW SP DFS XKC MAA JT GW CCC.

Interpreted the data: DA CRY JT CCC.

Contributed reagents/materials/analysis tools: CGE TWO RFM SW AS CCC.

Wrote the paper: DA.

We would like to thank Jayakrishna Ambati (University of Kentucky) and Lois Smith (Harvard Medical School) for their critical review of the manuscript. We gratefully acknowledge the NIH Histology Core for their services regarding routine histology and immunohistochemistry.

The authors would also like to make explicit their collaboration with Genzyme Corp.

Three of the co-authors, GW, SW, and AS are employees of Genzyme, who funded their salaries.

GW and AS are listed as inventors on a patent application held by the company.

Patent application name: “Composition and Methods for Inhibiting Interleukin Pathways” and number WO 2009042162.

There are no further patents, products in development or marketed products to declare. .

This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials

Subjects:

Research Funding:

The National Eye Institute Intramural Research Program & Genzyme funded the work.

The funder Genzyme provided support in the form of salaries for authors GW, SW, and AS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MULTIDISCIPLINARY SCIENCES
  • NLRP3 INFLAMMASOME
  • PIGMENT EPITHELIUM
  • THERAPEUTIC LEVELS
  • MICE
  • IL-17
  • CELLS
  • NEOVASCULARIZATION
  • COMPLEMENT
  • ACTIVATION
  • EXPRESSION

Interleukin-17 Retinotoxicity Is Prevented by Gene Transfer of a Soluble Interleukin-17 Receptor Acting as a Cytokine Blocker: Implications for Age-Related Macular Degeneration

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Journal Title:

PLoS ONE

Volume:

Volume 9, Number 4

Publisher:

, Pages e95900-e95900

Type of Work:

Article | Final Publisher PDF

Abstract:

Age-related macular degeneration (AMD) is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE) and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Universal : Public Domain Dedication License (http://creativecommons.org/publicdomain/zero/1.0/).

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